Suleiman-El-Hattab syndrome: a histone modification disorder caused by TASP1 deficiency

Abstract

Background TASP1 encodes an endopeptidase activating histone methyltransferases of the KMT2 family. Homozygous loss-of-function variants in TASP1 have recently been associated with Suleiman-El-Hattab syndrome. We report six individuals with Suleiman-El-Hattab syndrome and provide functional characterization of this novel histone modification disorder in a multi-omics approach. Methods Chromosomal microarray/exome sequencing in all individuals. Western blotting from fibroblasts in two individuals. RNA sequencing and proteomics from fibroblasts in one individual. Methylome analysis from blood in two individuals. Knock-out of tasp1 orthologue in zebrafish and phenotyping. Results All individuals had biallelic TASP1 loss-of-function variants and a phenotype including developmental delay, multiple congenital anomalies (including cardiovascular and posterior fossa malformations), a distinct facial appearance, and happy demeanor. Western blot revealed absence of TASP1. RNA sequencing/proteomics showed HOX gene downregulation (HOXA4, HOXA7, HOXA1, HOXB2) and dysregulation of transcription factor TFIIA. A distinct methylation profile intermediate between control and Kabuki syndrome (KMT2D) profiles could be produced. Zebrafish tasp1 knock-out revealed smaller head size and abnormal cranial cartilage formation in tasp1 crispants. Conclusion This work further delineates Suleiman-El-Hattab syndrome, a recognizable neurodevelopmental syndrome. Possible downstream mechanisms of TASP1 deficiency include perturbed HOX gene expression and dysregulated TFIIA complex. Methylation pattern suggests that Suleiman-El-Hattab syndrome can be categorized into the group of histone modification disorders including Wiedemann-Steiner and Kabuki syndrome.

Disorders of histone methylation: Molecular basis and clinical syndromes

“…For example, TASP1 also regulates the transcription factor TFIIA, therefore TASP1 deficiency can result in TFIIA dysregulation. 20 In addition, histone methylation can be an initial step that allows subsequent additional histone modifications. Therefore, a defect in histone methylation can result in impairment of other modifications and broader impact on gene expression.…”

“…53,54 Affected individuals have developmental delay (motor and speech), with less than 10 cases reported to date. 14,20,55 All affected individuals have developmental delay with severe speech delay, motor delay, hypotonia, and microcephaly. Other com- 1).…”

“…Some of these enzymes can regulate proteins other than histones. For example, TASP1 also regulates the transcription factor TFIIA, therefore TASP1 deficiency can result in TFIIA dysregulation 20 . In addition, histone methylation can be an initial step that allows subsequent additional histone modifications.…”

“…The prevalence is unknown. It was first described in 2019 with less than 10 cases reported to date 14,20,55 …”

“…Distinctive facial features include thick and arched eyebrows, synophrys, thick eyelids, periorbital fullness, epicanthal folds, broad nasal bridge, wide mouth, long smooth philtrum, thin upper and thick lower lip, and low‐set dysplastic ears. Congenital anomalies include brain malformations (posterior fossa malformations), heart anomalies (ventricular septal defects, atrial septal defects, tetralogy of Fallot), limb and skeletal deformities (short stature, shortened extremities, brachydactyly, and polydactyly), and cryptorchidism 14,20,55 …”